Method for producing heterocyclic acid anhydrides

ABSTRACT

A method for producing heterocyclic acid anhydrides and pyrimidinediones from the corresponding acids, dicarboxamides, 2,3-and 3,4-pyridinedicarboxamides, and N-monosubstituted 2,3-and 3,4-pyridinedicarboxamides, in which the aforesaid compounds are reacted with lead tetra-acetate in the presence of a suitable anhydrous inert solvent. Heterocyclic acid anhydrides are useful as intermediates in the production of pharmaceuticals, agricultural chemicals, and anthranilic acid esters used as perfume essences and flavoring materials. Pyrimidinediones and ring substituted analogues are useful as agricultural chemicals, especially as herbicides.

United States Patent [1 1 Beckwith June 3, 1975 METHOD FOR PRODUCINGIIETEROCYCLIC ACID ANIIYDRIDES [75] Inventor: Athelstan L. J. Beckwith,Adelaide,

Australia [73] Assignee: The Sherwin-Williams Company,

Cleveland, Okla.

22 Filed: Nov. 20, 1969 21 App]. No; 878,552

[52] US. Cl 260/244 R; 71/88; 71/92; 260/244 A; 260/256.4 F; 260/256.4R;

[51] Int. Cl C07d 87/10 [58] Field of Search....'...' 260/244 R, 244 A[56] References Cited FOREIGN PATENTS OR APPLICATIONS 1,135,789 12/1968United Kingdom 260/244 A OTHER PUBLICATIONS Beckwith et al., (Beckwithand Hickman), J. Chem.

(1968), QD1.A51.

Grob et al., Chem. Abst., Vol. 53, column 1274 (1959), QD1.A51

McKee, Fiveand Six-Membered Compounds with Nitrogen and Oxygen, p. 364,N.Y., Interscience-Wiley, 1962. QD401.F58.

Tufariello et al., Chem. Abst., Vol. 66, No. 55086a (1967),QD1.A51.

Primary Examiner-Natalie Trousof Attorney, Agent, or FirmOwen & Owen Co.

[57 ABSTRACT A method for producing heterocyclic acid anhydrides andpyrimidinediones from the corresponding acids, dicarboxamides, 2,3-and3,4-pyridinedicarboxamides, and N-monosubstituted 2,3 -and 3 ,4-pyridinedicarboxamides, in which the aforesaid compounds are reactedwith lead tetra-acetate in the presence of a suitable anhydrous inertsolvent.

Heterocyclic acid anhydrides are useful as intermediates in theproduction of pharmaceuticals, agricultural chemicals, and anthranilicacid esters used as perfume essences and flavoring materials.Pyrimidinediones and ring substituted analogues are useful asagricultural chemicals, especially as herbicides.

3 Claims, No Drawings METHOD FOR PRODUCING HETEROCYCLIC ACID ANHYDRIDESBACKGROUND OF THE INVENTION *U.S. 3,170,955 (1965) *U.S. 3,162,684(1964) *U.S. 3,163,646 (1964) *U.S. 3,120,523 (1964) *Neth. Apl.6,407,857 (1965) *U.S. 3,252,986 (1966) *U.S. 3,274,194 (1966) UBritish894,435 (1962) .**British 865,735 (1961 **U.S. 3,244,503 (1966) Germany1,210,242 (1966) Many of the pyrimidinediones and ring substitutedanalogues formed by the method of the invention are useful asagricultural chemicals, in particular as herbicldes. Specifically, manyof the compounds have been found to have utility as plant growthregulators, total herbicides, selective weed killers, and defoliatingagents.

In recent years increased crop yields have been made possible by thedevelopment and use of chemicals which are specifically toxic to weeds,yet do not damage crops around which they are applied. In general, thecurrently available chemicals which are most desired for theirselectivity and as total herbicides are sufficiently expensive that costis a significant factor in their use. Therefore, new compounds andinexpensive methods for producing such compounds are constantly beingsought. The use of 3-substituted pyrimidinediones is disclosed inapplication Ser. No. 740,090, filed June 26, 1968, now abandoned.

In addition, while many compounds presently on the market are effectiveagainst certain species of weeds, they are ineffective against others,or against certain strains or weeds. Apparently, resistant strainsdevelop by a phenomenon be can e likened to natural selection. Thusnewherbicides which have broad spectrum effectiveness against a widevariety of weeds are continually being sought.

It is an object of the present invention to provide an improved methodfor producing heterocyclic acid anhydrides and pyrimidinediones.

It is a further object to provide a method for the production ofheterocyclic acid anhydrides and pyrimidmediones which is non-hazardousand simple, and wh ch does not require exotic or expensive startingmaterials or complicated apparatus.

It is a further object of the invention to provide an easy one-stepmethod for the production of compounds having the following formulas:

Y W, X, Y and Z can be N, and R is hydrogen or an alkyl C 4 i i l c=oY\Z N w C ix Li -R i 1 i /C=O wherein each of W, X, Y and Z is N or CHand, in the acid anhydride, not more than one of X, Y and Z is N, while,in the pyrimidinediones, not more than two of group having not more than8 carbon atoms.* Alkyl group is used in the ordinary sense of the wordto indicate a straight-chain alkyl group.

BRIEF SUMMARY OF THE INVENTION The method of the instant inventioncomprises reaction in an inert anhydrous solvent (1) substantiallyequivalent amounts of lead tetra-acetate with (2) a compound having theformula wherein each of A and A is 01-1 or NHR and W, X, Y, Z and R havethe meanings. set forth above, with the proviso that not more than oneof A and A is 01-1 and when either of A and A is OH, R is hydrogen, W isCH and not more than one of X, Y and N, is n, agitating the reactionmixture at a temperature sufficiently high that reaction occurs andrecovering the acid anhydride or pyrimidinedione.

PREPARATION OF STARTING MATERIALS Compounds represented by the foregoingformula, when either of A and A is 01-1, are phthalamic acid andringsubstituted nitrogen analogues, named as carbamylnicotinic acids,which constitute the starting materials for the preparation of the acidanhydrides, they can be prepared as described in the references cited inExamples I through V.

Pyridine-2,3-and 3,4-dicarboxamides and N- monosubstituted 2,3-and3,4-pyridinedicarboxamides which constitute the starting materials forthe preparation of pyrimidinediones, can be made from correspondingdicarboxylic acids according to the method outlined below, through theimide, which is then reacted with NHg or a suitable amine. Thepreparation of N -n-butyl-2,3-pyridinedicarboxamide is used as anexample.

EXAMPLE A A 2-liter, 3-necked flask equipped with a stirrer and athermometer, and partially immersed in an oil bath was charged with 400g. of 2,3-pyridinedicarboxylic acid, 400 g. acetamide, and 400 ml.acetic anhydride. Agitation was begun and continued throughout thereaction. The reaction mixture was then heated rapidly to a temperatureof 136* and held at that temperature for 2 hours. During this period theacetic acid which was produced was distilled off. At the end of thistime, the mixture was cooled, the solids removed by filtration, and thefiltrate set aside. The solids were washed with cold methanol, dried,and weighed. The yield was 251.6 g. light tan material having a meltingpoint of 239240. The filtrate, which had been set aside, was reduced involume and a further yield of 9.2 g. of imide having a melting point of239240 obtained. The total yield was 260.8 g. 2,3-pyridinedicarboximide.The 2,3- pyridinedicarboximide was used to prepare N -n-butyl- 2,3-pyridinedicarboxamide in the following manner. All temperaturesreported herein and in the attached claims are in degrees Centrigrade.

A 500 ml. flask equipped with a stirrer, condenser, thermometer,bubbler, and addition funnel, and partially immersed in an ice bath, wascharged with 16.5 g. pyridinedicarboximide and 100 ml. benzene.Agitation of the flask contents was begun and continued throughout theduration of the reaction. An addition of 11.0 g. n-butylamine was thencommenced and charged over a 2 minute period. After the charging, thereaction mixture was stirred for an additional two hours and 30 minutes,during which time the temperature of the reaction mixture reached a highof 45. At the end of this time, the thick slurry which had formed wascooled to about the solids were removed by filtration, and the filtratewas set aside. The solids were then washed with cold benzene and dried.The yield was 21.4 g. product which had a melting point of 8795, and wasidentified by infrared spectroscopy as a mixture consistingpredominately of N -n-butyl-2,3- pyridinedicarboxamide with a smallamount of N -nbutyl-2,3-pyridinedicarboxamide.

The unsubstituted 2,3- and 3,4-dicarboxamides of pyridine and the otherN-monosubstituted 2,3- and 3,4- dicarboxamides of pyridine can beproduced in the same manner by reaction of the corresponding imide withthe appropriate amine or NH The reaction can be illustrated as follows:

9 O OH CH3CONH2 (CH CO)2O I g-oH 2,3-pyridinedicarboxylic acid 2E-pyridinedi carboximi de This invention can be more clearly understoodby reference to the following examples.

EXAMPLE I PREPARATION OF lSATOlC ANHYDRIDE A 250 ml. flask was chargedwith 2.0 g. phthalamic acid* suspended in 100 ml. dry benzene, andheated to boiling. A 5.4 g. portion of lead tetra-acetate was added tothe boiling suspension, and the reaction mixture was heated underreflux, with stirring, for 48 hours. The reaction mixture was thencooled and solids were separated therefrom by filtration. The residuewas washed 2 times with water; isatoic anhydride was recrystallized fromdioxane, and dried in vacuo for 2 hours. The final yield of isatoicanhydride amounted to 0.87 g. tan solids, melting point 243, andrepresented 44 percent of theory based on the phthalamic acid. Thestructure was confirmed by infrared spectroscopy. E. Chapman and H.Stephen, J. Chem. Soc., 1925, 127,1791

EXAMPLE ll PREPARATION OF lSATOlC ANHYDRIDE EXAMPLE lll PREPARATION OF 3-AZAISATOIC ANHYDRIDE A 100 ml. flask was charged with 2.0 g.Z-carbamylnicotinic acid* suspended in 20 ml. dimethylformamide. A 5.5g. portion of lead tetra-acetate was added to the suspension, and themixture was stirred at 5060 for 1 hour. The reaction mixture was pouredinto 20 ml. water; solids were separated by filtration,

NH BCHSCOOH 2 B-pyridine dicar'boximide pyri dinedicarboxamide and3-azaisatoic anhydride was recrystallized from dioxane, and dried invacuo for 2 hours. The final yield of 3-azaisatoic anhydride amounted to1.48 g., melting point 2l7219, and represented 75 percent of theory. Thestructure was confirmed by elemental analysis and infrared spectroscopy.

F. G. Mann and .l. A. Reid, J. Chem. Soc., 1952, 2057; the referencediscloses that: In the earlier work, [1. Chem. Soc. 1951, 7611 2-aminonicotinic acid was prepared from quinolinic imide: we now find farbetter to start with quinolinicanhydride, which is converted by gaseousammonia into 2-carbamylnicotinic acid"... citing F ibel and Spoerri J.Am. Chem. Soc.. 1948, 70, 3908.

EXAMPLE IV PREPARATION OF 4-AZAISATOIC ANI-IYDRIDE A 50 ml. flask wascharged with 0.94 g. 3- carbamylisonicotinic acid suspended in 8 ml.dimethylformamide. A 2.5 g. portion of lead tetra-acetate was added tothe suspension, and the reaction mixture was stirred at 20 for 10minutes. The reaction mixture was then warmed to 45 and stirred for 10minutes. The cooled mixture was poured onto 30 grams crushed ice and thepale yellow solids were collected by filtration and dried in vacuo.Extensive decomposition of the product occurred upon attemptedrecrystallization from organic solvents. The final yield of 4-azaisatoicanhydride amounted to 0.65 g., melting point 218, with decomposition,and represented 70 percent of the ory. The structure was identified byelemental analysis, infrared spectroscopy and mass spectrometry.

EXAMPLE V PREPARATION OF S-AZAISATOIC ANI-IYDRIDE A 50 ml. flask wascharged with 2.6 g. lead tetraacetate suspended in 10 ml.dimethylformamide and stirred while a solution of 0.96 g. of4-carbamylnicotinic acid in 5 ml. dimethylformamide was added dropwiseduring 10 minutes. The mixture was stirred for 10 minutes aftercompletion of the addition, then poured onto 40 g. crushed ice. Aprecipitate of cream solids was collected by filtration, washed withwater and dried in vacuo. The yield of S-azaisatoic anhydride amountedto 0.68 g., melting point 180 with decomposition, and represented 72percent of theory. On attempted purification by crystallization fromorganic solvents, extensive decomposition occurred. The structure wasconfirmed by elemental analysis, infra-red spectroscopy and massspectrometry.

EXAMPLE VI PREPARATION OF PYRAZINO[2,3-d]PYRIMIDlNE-2,4( lI-I,3H)-

DIONE A 50 ml. flask was charged with 0.90 g. pyrazine-2,3-dicarboxamide dissolved in 16 ml. dimethylformamide. A 2.4 g. portion oflead tetra acetate was added to the solution and the reaction mixturewas stirred at 400 for minutes. The reaction mixture was cooled, 30 g.of ice was added and after 1 hour the mixture was filtered.Crystallization of the residue from water gave, after drying in vacuo, ayield of 0.64 g. of pyrazino[2,3- d]pyrimidine-2,4(1ll,3l-I)-dione,melting point 364365, which represented 71 percent of theory. Thestructure was confirmed by infra-red spectroscopy.

EXAMPLE VII PREPARATION OF 2,4( lI-I,3H)-QUINAZOLINEDIONE A 50 ml. flaskwas charge d with 1.0 g. phthalamide EXAMPLE VIII PREPARATION OF PYRIDO[2,3-d]PYRIMIDINE-2,4( 1 I-I,3H )-DIONE A 50 m1. flask was charged with0.9 g. pyridine-2,3- dicarboxamide suspended in 10 ml.dimethylformamide. A 2.4 g. portion of lead tetra-acetate was added tothe suspension, and the reaction mixture was stirred at 5060 for 20minutes and filtered. Sublimation of the residue at 200 at an absolutepressure of 0.01 mm. Hg gave a yield of 0.8 g. pyrido[2,3-d]pyrimidine-2,4( lH,3H)-dione, melting point 360, and represented percent of theorybased on the pyridine-2,3- dicarboxamide. The structure was confirmed byinfrared spectroscopy.

EXAMPLE IX PREPARATION OF PYRIDO[3,4-d]PYRIMIDINE-2,4(1H,3H)DIONE A 50ml. flask was charged with 1.0 g. pyridine-3,4- dicarboxamide suspendedin 10 ml. dimethylformamide. A 2.4 g. portion of lead tetra-acetate wasadded to the suspension, the reaction mixture stirred at 50-60 for 1hour. Cooled and filtered. Sublimation of the residue at 210/0.01 mm.gave a yield of 1.0 g. of pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione,melting point 365, representing percent of theory based on thepyridine-3,4-dicarboxamide. The structure was confirmed by elementalanalysis and infrared spectroscopy.

EXAMPLE X PREPARATION OF 3-METI-IYL-2,4( lH,3H)-QUINAZOLINEDIONE A 50ml. flask was charged with 1.0 g. N- methylphthalamide suspended in l 1ml. dimethylformamide. A 2.6 g. portion of lead tetra-acetate was addedto the suspension, and the reaction mixture stirred at 40-50 for 2hours. The reaction mixture was diluted with 15 ml. water, cooled andfiltered. The yield amounted to 0.89 g., melting point 230-232,representing 88 percent of theory based on the N- methylphthalamide. Thestructure was confirmed by infrared spectroscopy.

EXAMPLE XI PREPARATION OF 3-n-BUTYL-PYRIDO[ 3 ,2- d]PYRIMIDINE-2,4(lI-I,3H)-DIONE A 100 ml. flask was charged with 9.0 g. of a mixture of N-n-butyl-2,3-pyridine-dicarboxamide and N-nbutyl-Z,3-pyridine-dicarboxamide suspended in 70 g. dimethylformamide.An 18.0 g. portion of lead tetraacetate was added, and the reactionmixture stirred at 60 for 2 hours. The reaction mixture was poured into200 ml. water. The precipitate was filtered from the water,recrystallized from dioxane, and dried at 100,

for about 1 hour. The final yield of 3-n-butylpyrido[3,2-d] and3-n-butyl-pyrido[2,3-d]pyrimidine- 2,4(1H,3I-I)-dione amounted to 8.4g., melting point 200210, and represented 93 percent of theory based onthe dicarboxamide starting material. The structure was determined bynuclear magnetic resonance spectros consist of 78 percent of the[3,2-d1isomer and 22 percent of the [2,3-d1isomer.

EXAMPLE XII PREPARATION OF B-METHYL PYRAZINO[2,3-d]PYRIMIDINE-2,4(1H,3H)-

DIONE A 50 ml. flask was charged with 0.90 g. N-methylpyrazine-2,3-dicarboxamide dissolved in 16 ml. dimethylformamide.A 2.4 g. portion of lead tetraacetate was added to the solution and thereaction mixture was stirred at 25 for minutes. The reaction mixture wascooled, 30 g. of ice was added and after 1 hour the mixture wasfiltered. Crystallization of the residue from a mixture of water anddimethylformamide gave, after drying in vacuo, a yield of 0.76 g. of 3-methylpyrazine[2,3-d]pyrimidine-2,4( lI-I,3I-I)-dione, melting point342-343, which represented 86 percent of theory. The structure wasconfirmed by elemental analysis, infra-red spectroscopy and massspectrometry.

DISCUSSION OF THE REACTION MEDIUM The improved method of the inventioncan be carried out in various inert, anhydrous solvents and combinationsof such solvents. Although the reaction proceeds in a non-polar solventsuch as benzene, as illustrated in Example I, dipolar aprotic solventsare the preferred reaction medium. The presence of a dipole moment (u)in such a dipolar aprotic solvent molecule contributes to the ease ofsolubility of the reacting compounds and to an improved reaction whichtakes place more readily than in a non-polar reaction medium. Thereactions in dipolar aprotic solvents can be carried out at a lowertemperature and will proceed at a much faster rate than reactionscarried out in non-polar solvents. The preferred dipolar aproticsolvents of the method of the invention are: dimethylformamide,diethylformamide, dimethylacetamide, diethylacetamide, anddimethylsulfoxide. Aromatic solvents which are operable as reactionmedia are benzene, ethylbenzene, xylene, toluene, and pyridine.Combinations of dipolar solvents and combinations of dipolar andaromatic solvents are also operable as reaction media.

In addition to being useful as discussed above, acid anhydrides producedby the method of the invention are useful as intermediates for theproduction of pyrimidine diones which can be used as herbicides. Forexample, 3-azaisatoic anhydride can be dissolved in dimethylformamideand reacted with a substantially stoichiometric amount of isopropylamine to produce 2- amino-N-isopropylnicotinamide. The reaction isconveniently conducted at a temperature of about 45-50 until carbondioxide evolution ceases. The Z-amino-N- isopropylnicotinamide can thenbe reacted with phosgene to produce 3-isopropyl pyrido[2,3-d]pyrimidine-2,4( lI-I,3H)-dione. This reaction can be conducted under ambientpressure in p-dioxane as a solvent, preferably in the presence oftriethylamine as an HCl absorber, at a temperature in the vicinity of100.

The 3-isopropyl pyrido[2,3-d]pyrimidine- 2,4( lH,3I-l)-dione for which3-azaisatoic anhydride is an intermediate, as discussed above, can beused as a herbicide, dissolved in acetone, by spraying onto soil whichhas been prepared for planting. A light working of the soil after sprayapplication is desirable, e.g., by dragging or disking-to work the3-isopropyl pyrido[2,3- d]pyrimidine-2,4(lH,3H)-dione into the soil. Thesoil can then be planted in a conventional manner. The 3- isopropylpyridol2,3-d]pyrimidine-2,4(lH,3H)-dione, applied at a rate of 16 poundsper acre, is innocuous to alfalfa, but shows herbicidal activity againstvolunteer corn, wild oats, cheat grass, foxtail, barnyard, crab grass,nut grass, Johnson grass, volunteer snap beans, soybeans, pig weed,lambsquarter and marigold and, at higher application rates, can be usedas a total herbicide.

The 2-amino-N-isopropylnicotinamide for which 3- azaisotoic anhydride isan intermediate, as also discussed above, can also be dissolved inacetone and used as described in the preceding paragraph hereof at anapplication rate of 16 pounds per acre as a preemergence herbicide forthe control of wild oats.

The 4-azaisatoic anhydride and the S-azaisatoic anhydride, produced asdescribed above according to the method of the invention, are believedto be new compounds, all attempts at their production by an aqueousHoffman reaction which has been used to produce 3- azaisatoic anhydridehaving failed. The 4- and 5- azaisatoic anhydrides are also useful aschemical intermediates. They undergo reactions analogous to thosediscussed above with isopropyl and other amines to produce the isomericN-substituted amides, from which the isomeric pyrimidine diones canlikewise be produced by reaction with phosgene.

Some of the pyrimidine diones produced by the method of the inventionare useful as herbicides. For example, 3-n-butyl pyrido[ 3,2-d]pyrimidine- 2,4( lI-I,3I-l)-dione, applied as described at a rateof 16 lbs. per acre, was found to provide 100 percent control ofalfalfa, corn, wild oats, cheatgrass, foxtail, barnyard grass, nutgrass,Johnsongrass, snapbeans, yellow rocket, chickweed, cucumber, pigweed andvelvetleaf, percent control of lambsquarters and percent control ofcrabgrass.

The pyrimidine diones produced by the method of the invention which arenot particularly useful as herbicides are unexpectedly useful because oftheir close similarity, from a structural chemical standpoint, tocompounds having extremely high orders of activity. For example,3-n-butyl pyrazino[2,3-dlpyrimidine- 2,4(lH,3H)-dione has a considerablylower order of herbicidal activity than does 3-n-butyl pyrido[3,2-d]pyrimidine-2,4(lH,3H)-dione, and members of other families ofpyrimidine diones produced by the method of the invention aresubstantially inert as herbicides. The close structural similaritiesamong these several compounds, coupled with the fact reported herein ofthe significant difference in order of herbicidal activ ity provides thebasis for an orderly investigation, on the basis of molecular models, ofthe relationship between chemical structure and herbicidal activity, thedevelopment of a theory explaining this relationship, and consequentsignificant advance in the useful arts on the basis of intelligentapplication of the theoretical explanation by skilled workers in theart.

The pyrimidine diones produced by the method of the invention are alsouseful as ingredients of suntan lotions, because they absorb ultravioletradiation in the burning spectrum, being substantial equivalents for thecommercially used salicylates for which they can be substituted incommercial lotions. In addition, they are corrosion inhibitors, usefulin pickling baths and the like. The corrosion inhibiting characteristicsof the pyrimidine diones produced by the method of the invention havebeen demonstrated by immersing carefully cleaned, dried and weighed 1010steel coupons in percent sulfuric acid to which a minor amount of thepyrimidine dione has been added for a period of 4 hours at 75 and thenagain carefully cleaning, washing, drying and weighing the coupons. Thepercentage weight loss, which is 100 times the weight loss in gramsdivided by the weight of the coupon, inhibited versus uninhibited 5percent sulfuric acid, indicates that the pyrimidine diones produced bythe method of the invention are useful as corrosion inhibitors.

The acid anhydrides produced by the method of the invention, as has beenindicated above, can be converted to pyrimidine diones by reaction withan appropriate amine and ring-closure with phosgene. The correspondingsulfur analogues can also be produced by ring-closure with thiophosgenethese analogues are preferred as corrosion inhibitors becauseequilibrium favors the CSH form rather than the favored C=O form of thediones.

I claim:

1. A method for producing heterocyclic acid anhydrides having theformula,

wherein each of X, Y and Z is N or CH and, not more than one of X, Y andZ is N, said method comprising dissolving in an inert anhydrous solventsubstantially equivalent amounts of lead tetraacetate and a compoundhaving the formula O x Q A l l 9 u A ond named reactant isZ-carbamylnicotinic acid.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent 3,887,550Dated June 3. 1975 Q Inv nt fls) Athelstan L. J. Beckwith It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

In the heading of the patent [73] the address of the assignee isCleveland, Ohio.

Signed and Sealed this second Day Of September 1975 [SEAL] Arrest:

RUTH C. MASON C. MARSHALL DANN Atu'sling Officer (mnmissimu'r uflatenlsand Trademarks FORM PO-1 (10-69) USCOMM-DC 60376-P69 k LLS. GOVERNMENTPRINTING OFFICE 1 I969 0-366-33L

1. A METHOD FOR PRODUCING HETEROCYCLIC ACID ANHYDRIDES HAVING THEFORMULA,
 1. A method for producing heterocyclic acid anhydrides havingthe formula,
 2. A method as claimed in claim 1 wherein the second namedreactant is phthalamic acid.